EP0361873B1 - Enterische Beschichtung und ihre Herstellung - Google Patents

Enterische Beschichtung und ihre Herstellung Download PDF

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Publication number
EP0361873B1
EP0361873B1 EP89309801A EP89309801A EP0361873B1 EP 0361873 B1 EP0361873 B1 EP 0361873B1 EP 89309801 A EP89309801 A EP 89309801A EP 89309801 A EP89309801 A EP 89309801A EP 0361873 B1 EP0361873 B1 EP 0361873B1
Authority
EP
European Patent Office
Prior art keywords
enteric
solution
polyethylene glycol
granules
weight percent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89309801A
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English (en)
French (fr)
Other versions
EP0361873A2 (de
EP0361873A3 (de
Inventor
Shunichi Itoh
Hiroyoshi Koyama
Shin-Ichiro 201 Tamamoto-Cho Hirai
Toshio Kashihara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to AT89309801T priority Critical patent/ATE92753T1/de
Publication of EP0361873A2 publication Critical patent/EP0361873A2/de
Publication of EP0361873A3 publication Critical patent/EP0361873A3/de
Application granted granted Critical
Publication of EP0361873B1 publication Critical patent/EP0361873B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • This invention relates to enteric films having improved strength, thus being usable in such fields as foods and pharmaceuticals.
  • enteric coating of pharmaceutical preparations has been carried out for the purposes of the protection of the active ingredient susceptible to acid attack from the gastric juice and the drug-release controlled system (or the drug delivery system).
  • the intended purpose has been heretofore achieved by covering tablet surfaces with the coating.
  • the reports were published that the enteric-coated granules, when compared with the enteric-coated tablets from a biopharmaceutical point of view, do not produce individual variation in gastric emptying rate and absorption and is almost free from influence by meals, and as an example of such granules, there may be mentioned the aspirin preparation [C. Bogentoft, et al.; Eur. J. Clin. Pharmacol., 14 , 351 - 355 (1978) and A. Anslow et al.; Current Therapeutic Research, 36 (5), 811 - 818 (1984)].
  • WO 87/05505 discloses an enteric coating comprising hydroxypropylmethylcellulose phthalate, polyethylene glycol and shellac.
  • the present inventors conducted intensive investigation into the coating base which is usable in the processing and manufacture of enteric granules and enteric powder having increased film strength and as a result, found that when hydroxypropylmethylcellulose phthalate having specifically defined properties, shellac and polyethylene glycol are combined at a specific ratio to conduct enteric coating, there unexpectedly result enteric pharmaceutical preparations with enhanced film strength and furthermore that in cases where they are processed into other types of pharmaceutical preparations such as tablets and capsules, such preparations can withstand mechanical shock or impact, thereby leading to the completion of this invention.
  • HPMCP Hydroxypropylmethylcellulose phthalate
  • HP-55S produced by Shin-Etsu Chemical Co., Ltd., Tokyo, Japan.
  • Polyethylene glycol (hereinafter referred to in some instances as "PEG") as used in this invention presents the solid form at ambient temperature (15 to 25°C) and shows normally a mean molecular weight of 1,200 to 25,000, preferably 2,000 to 10,000, more preferably 7,000 to 9,500. Its specific examples include PEG 1500, PEG 4000, PEG 6000 and PEG 20000.
  • the enteric film of this invention is obtained by covering a pharmaceutical preparation intended to be provided with enteric property with an enteric coating agent consisting of HPMCP, PEG and shellac being formulated at the previously mentioned ratio.
  • the pharmaceutical preparation to be covered with the said enteric film is not specifically limited, only if it includes powders, fine granules, granules, pills, tablets, capsules and pharmaceutically processed products thereof (for example, the products produced by processing enteric granules into tablets or capsules).
  • the active ingredient to be incorporated into these pharmaceutical preparations is not specifically limited, only if it can be incorporated into the preparations for the purpose of enteric property, and includes, for example, drug substances for the central nervous system, such as diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, dichlofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, and ketoprofen; cardiovascular drugs, such as molsidomine, vinpocetine, propranolol, methyldopa, dipyridamol, furosemide, triamteren, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril and isosobide dinitrate; drugs for respiratory organs, such as
  • solvent which is used to dissolve HPMCP, PEG and shellac in this invention there may be mentioned, for example, mixtures of acetone and ethanol and mixtures of ethanol and water, and alcohols such as isopropanol and n-propanol may be added, if necessary.
  • HPMCP is desirably dissolved in acetone, whereupon the mixing ratio of HPMCP against acetone is normally 3 to 15 weight %, preferably 6 to 10 weight %.
  • the mixing ratio of less than 3 % because of the lowered concentration of HPMCP, requires a prolonged period of time to perform the coating in sufficient amounts enough to secure adequate enteric property and is not preferable.
  • the mixing ratio of not less than 20 % results in increased viscosity of the solution, bringing about troubles during coating.
  • the enteric coating solution is preferably produced by mixing an acetone solution of HPMCP with an ethanol solution of PEG and shellac.
  • an ethanol solution of PEG and shellac When the said ethanol solution is mixed with the said acetone solution at a ratio of 10 to 100 weight % against the acetone solution, particularly 10 to 70 weight %, there can be obtained the solution mixture free from insoluble matter.
  • the enteric coating solution thus mixed is sprayed onto the objective preprations to give enteric coated pharmaceutical preparations.
  • PEG is normally contained at a ratio of 0.1 to 20 weight %, preferably 2 to 10 weight %, while shellac usually at a ratio of 5 to 40 weight %, preferably 15 to 35 weight %, as expressed on the basis of HPMCP.
  • the three-component compositions are soluble in a mixture consisting of 75 to 85 weight % of alcohol and 15 to 25 weight % of water, particularly in a mixture consisting of 78 to 82 weight % of alcohol and 18 to 22 weight % of water, and when the content of HPMCP in the said mixture is normally at a ratio of 1 to 10 weight %, with PEG and shellac being contained at the above mentioned ratios, excellent enteric coating solutions can be obtained.
  • the enteric coated tablets are obtained for example by placing plain tablets in a ventilated coating machine followed by spraying with the coating solution, whereby no limitation is posed on the type of pharmaceutical preparations to be used for coating.
  • the temperature of the coating solution during production is not specifically required to be adjusted and may usually be at room temperature (1 to 30°C).
  • core granules are placed in a fluidized coating machine and sprayed with the coating solution without controlling the temperature of the solution as is the case with the coating of tablets.
  • the enteric coated preparations obtained by this procedure may be further treated by means of the per se known method for the purpose of printing or polishing.
  • the enteric film according to the present invention excels in film strength and acid resistance, and consequently, pharmaceutical preparations such as granules, powders and tablets can be covered with said enteric films to produce the enteric-coated pharamaceutical preparations with increased film strength.
  • enteric coating solution of the following composition at a rate of 50 ml/minute, under the inlet air temperature and product temperature being controlled at 60°C and 45°C, respectively, to give enteric-coated granules.
  • the resulting granules were found to be almost free from granule breaking and binding together among granules during coating, being covered uniformly with enteric films, and to pass the particle size test (the particle size as granules specified in the Japanese Pharmacopeia, llth revised edition.
  • CF granulator manufactured by Freund Co.
  • Nonpareil® 24 to 32 mesh
  • granulation was performed while spraying with the in-advance prepared coating solution of the following composition at a rate of 200 ml/minute x 2 guns.
  • the granulated material was vacuum-dried at 40°C for 16 hours and sifted through a sieve to give spherical cored granules of 12 to 32 mesh.
  • FM-G25 type vertical granulator
  • the resultant white kneaded material was dried in a fluidized-bed dryer (FD-3S, manufactured by Fuji Sangyo Co.) at the air blowing temperature of 60°C and passed through a power mill with 1.5 mm ⁇ punching screen (P-3 type, manufactured by Showa Kagaku-Kikai Seisakusho Co.) to produce granules for tablet.
  • FD-3S fluidized-bed dryer
  • P-3 type manufactured by Showa Kagaku-Kikai Seisakusho Co.
  • a multiplex granulator (MP-25 type, manufactured by Fuju Sangyo Co.) were 500 g of serrapeptase, 3000 g of sucrose, 150 g of crystalline cellulose, 1050 g of corn starch, 150 g of Ac-Di-Sol® and 150 g of hydroxypropylcellulose, and 1450 g of water was added to carry out granulation (granulation conditions: 400 rpm for 15 minutes).
  • Example 5 polyethylene glycol 400 or acetylated monoglyceride (Mybarset® 9-40T), a liquid plasticiser, was used in place of polyethylene glycol 6000 to prepare the enteric coating solution, and the solution was sprayed to give enteric coated granules.
  • the resulting granules provided with enteric coating were found to be free from film peeling and surface roughness, being covered uniformly with enteric films.
  • the enteric-coated granules as obtained in Example 4 and Reference Examples 1 and 2 were mixed with crystalline cellulose at a ratio (enteric-coated granule: crystalline cellulose) of 1:2 and 1:5, and the mixture was compressed into tablets each weighing about 200 mg and measuring 8 mm ⁇ in outer diameter at a compression pressure of 1 ton/cm2 by use of Autograph (IS-5000, manufactured by Shimadzu Seisakusho Co. of Japan), whereby magnesium stearate was used as a lubricant.
  • Autograph IS-5000, manufactured by Shimadzu Seisakusho Co. of Japan
  • the resulting tablets were placed in an auxiliary tube to be used in the disintegration test for enteric-coated granules as specified in the Japanese Pharmacopeia, 11th revised edition, then shaked in the first solution for 60 minutes in accordance with the disintegration test for enteric-coated preparations, and the contents in the enteric-coated granules having remained in the auxiliary tube were measured by means of enzymatic assay.
  • the granules other than those covered with the entric films according to this invention were all found to show a great decrease in the contents and to be provided with enteric films of strength inferior to the enteric films of this invention.
  • Example 4 In the procedure of Example 4, the formulation amount of shellac alone was changed to 15 g and 385 g, while the one of polyethylene glycol 6000 alone being changed to 231 g, to prepare three different enteric coating solutions, and spraying was performed with these coating solutions to produce enteric-coated granules (Control sections 4, 5 and 6).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Polarising Elements (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)

Claims (10)

  1. Enterischer Film, welcher umfaßt:
    (a) Hydroxypropylmethylzellulosephthalat, das als 10%ige Lösung in Methanol/Dichlormethan (Gewichtsverhältnis 1:1) bei 20°C eine Viskosität von 1,36 x 10⁻⁴ bis 2,04 x 10⁻⁴ m²/s (136 bis 204 cSt) aufweist.
    (b) Polyäthylenglykol, das bei 15 bis 25°C in festem Zustand vorliegt, und
    (c) Schellack,
    wobei die Verhältnisse von (b) und (c) zu (a) 0,1 bis 20 Gew.-% bzw. 5 bis 40 Gew.-% betragen.
  2. Enterischer Film nach Anspruch 1, worin der Gehalt an Methoxyl-, Hydroxypropoxyl- und Carboxybenzoylgruppen im Hydroxypropylmethylzellulosephthalat 18,0 bis 22%, 5,0 bis 9,0% bzw. 27,0 bis 35,0% beträgt, und der mittlere Polymerisationsgrad des Hydroxypropylmethylzellulosephthalats bei etwa 240 liegt; und das Polyäthylenglykol bei 15 bis 25°C in festem Zustand vorliegt und ein mittleres Molekulargewicht von 1200 bis 25000, vorzugsweise 2000 bis 10000, mehr vorzuziehen 7000 bis 9500 aufweist.
  3. Enterischer Film nach Anspruch 1, worin das Polyäthylenglykol Polyäthylenglykol 1500, 4000, 6000 oder 20000 ist.
  4. Verfahren zur Herstellung eines enterischen Filmes, welches das Aufsprühen einer gemischten Lösung aus (a) Hydroxypropylmethylzellulosephthalat, das als 10%ige Lösung in Methanol/Dichlormethan (Gewichtsverhältnis 1:1) bei 20°C eine Viskosität von 1,36 x 10⁻⁴ bis 2,04 x 10⁻⁴ m²/s (136 bis 204 cSt) aufweist, (b) bei 15 bis 25°C in festem Zustand vorliegendem Polyäthylenglykol und (c) Schellack, wobei die jeweiligen Verhältnisse von (b) und (c) zu (a) 0,1 bis 20 Gew.-% bzw. 5 bis 40 Gew.-% betragen, auf ein Material und das anschließende Trocknen der Lösung umfaßt.
  5. Verfahren nach Anspruch 4, worin der Gehalt an Methoxyl-, Hydroxypropoxyl-  und Carboxybenzoylgruppen im Hydroxypropylmethylzellulosephthalat 18,0 bis 22 %, 5,0 bis 9,0 % bzw. 27,0 bis 35,0 % beträgt, und der mittlere Polymerisationsgrad des Hydroxypropylmethylzellulosephthalats bei etwa 240 liegt; und das Polyäthylenglykol bei 15 bis 25°C in festem Zustand vorliegt und ein mittleres Molekulargewicht von 1200 bis 25000, vorzugsweise 2000 bis 10000, mehr vorzuziehen 7000 bis 9500 aufweist.
  6. Verfahren nach Anspruch 4, worin das Polyäthylenglykol Polyäthylenglykol 1500, 4000, 6000 oder 20000 ist.
  7. Verfahren nach Anspruch 4, worin das Material Pulver, Feingranulat, Granulat, Pillen, Tabletten oder Kapseln ist.
  8. Verfahren nach Anspruch 4, worin die Lösung durch Verwenden einer Mischung aus Aceton und Äthanol oder Äthanol und Wasser als Lösungsmittel und weiters zusätzlich, wenn notwendig, Isopropanol oder normalem Propanol hergestellt wird.
  9. Verfahren nach Anspruch 4, worin die Lösung durch Mischen einer Lösung aus Hydroxypropylmethylzellulosephthalat in Aceton und einer Lösung aus Polyäthylenglykol und Schellack in Äthanol hergestellt wird.
  10. Verfahren nach Anspruch 9, worin die Konzentration des Hydroxypropylmethylzellulosephthalats in Aceton 3 bis 15 Gew.-%, vorzugsweise 6 bis 10 Gew.-%, die Konzentration des Polyäthylenglykols in Äthanol 0,1 bis 5 Gew.-%, vorzugsweise 0,5 bis 1,5 Gew.-%, und die Konzentration des Schellacks in Äthanol 1 bis 10 Gew.-%, vorzugsweise 3 bis 6 Gew.-%, beträgt.
EP89309801A 1988-09-27 1989-09-26 Enterische Beschichtung und ihre Herstellung Expired - Lifetime EP0361873B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89309801T ATE92753T1 (de) 1988-09-27 1989-09-26 Enterische beschichtung und ihre herstellung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP24354288 1988-09-27
JP243542/88 1988-09-27

Publications (3)

Publication Number Publication Date
EP0361873A2 EP0361873A2 (de) 1990-04-04
EP0361873A3 EP0361873A3 (de) 1991-01-30
EP0361873B1 true EP0361873B1 (de) 1993-08-11

Family

ID=17105427

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89309801A Expired - Lifetime EP0361873B1 (de) 1988-09-27 1989-09-26 Enterische Beschichtung und ihre Herstellung

Country Status (10)

Country Link
EP (1) EP0361873B1 (de)
KR (1) KR0134089B1 (de)
AT (1) ATE92753T1 (de)
AU (1) AU619047B2 (de)
CA (1) CA1337274C (de)
DE (1) DE68908320T2 (de)
DK (1) DK473989A (de)
ES (1) ES2058545T3 (de)
IE (1) IE64124B1 (de)
NZ (1) NZ230764A (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5124600A (en) * 1999-04-26 2000-11-10 Imperial Sensus, L.L.C. Granular delivery system

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3390049A (en) * 1964-12-23 1968-06-25 Smith Kline French Lab Pharmaceutical tablets coated with wax-free ammonia solubilized water soluble shellac
JPS57171428A (en) * 1981-04-13 1982-10-22 Sankyo Co Ltd Preparation of coated solid preparation
DE3234331C2 (de) * 1982-09-16 1986-06-05 A. Nattermann & Cie GmbH, 5000 Köln Verfahren und Lösungen zum Beschichten von Gelatinekapseln mit magensaftresistenten Überzügen
HU207452B (en) * 1986-03-21 1993-04-28 Eurasiam Lab Method for producing therapeutical preparations containing active ingredient having biologicallu active protein structure
JPS6327424A (ja) * 1986-07-17 1988-02-05 Shionogi & Co Ltd 徐放性製剤およびその製造法

Also Published As

Publication number Publication date
DE68908320D1 (de) 1993-09-16
ES2058545T3 (es) 1994-11-01
ATE92753T1 (de) 1993-08-15
DK473989D0 (da) 1989-09-26
CA1337274C (en) 1995-10-10
EP0361873A2 (de) 1990-04-04
NZ230764A (en) 1991-01-29
KR900004324A (ko) 1990-04-12
AU619047B2 (en) 1992-01-16
IE64124B1 (en) 1995-07-12
DE68908320T2 (de) 1994-02-24
IE893074L (en) 1990-03-27
DK473989A (da) 1990-03-28
AU4233089A (en) 1990-04-05
KR0134089B1 (ko) 1998-04-22
EP0361873A3 (de) 1991-01-30

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